Project 1, Abstract Mycobacterium tuberculosis (Mtb) has to adapt to acidic niches inside the host, which include macrophages phagosomes and the caseum of granulomas. Previous work led to the identification of acid resistance genes, that enable Mtb to survive severe acid stress. The key pathways and underlying mechanisms that that enable Mtb to adapt to and replicate in mildly acidic conditions, a requirement for its ability to transmit from one host to another, are incompletely understood. The central hypothesis driving this project is that exposure to acidic pH triggers a reprogramming of Mtb?s metabolism towards lipid and fatty acid catabolism which facilitates growth and remodeling of its cell surface lipids. We propose to (i) determine the importance of fatty acid and lipid metabolism from intra- and extracellular stores for adaptation to and growth at acidic pH, (ii) determine the impact of acid pH on Mtb?s cell envelope composition and define the importance of pH-dependent cell envelope remodeling for Mtb stress resistance and (iii) define the genetic and physical structure of pathways required for Mtb?s adaptation to and growth at acidic pH. These activities directly contribute to our overall program goal to understand key pathways in Mtb biology, with a particular focus on complex pathways that are important for the adaptation to disease-relevant stress.